To determine the potential contribution of coronary thrombus to severe chronic stable angina, thrombolytic therapy, using Ancrod, a snake venom derivative with defibrinogenating and indirect tissue plasminogen activator properties was given to 10 patients. After stopping medications, patients were randomized and treated blindly with either daily infusions of placebo or Ancrod for 2 weeks. Patients given placebo first were then given open-label Ancrod for 2 more weeks. Efficacy was assessed using exercise tests and radionuclide cineangiograms at rest and during matched levels of exercise. During Ancrod therapy, all patients increased exercise duration greater than 50% compared with pre-study control values and 3 patients with severe rest angina became symptom free. However, exercise duration was not associated with improved ST-segment changes, peak pressure rate product during exercise, or reduced radionuclide cineangiographic indices of ischemia. These data suggest that thrombolytic therapy using Ancrod in refractory angina improves exercise capacity in most patients, but the mechanism underlying beneficial responses and long-term efficacy remain undefined. This study is the first attempt to examine the possible role of thrombus formation in coronary syndromes other than acute myocardial infarction and the results should will stimulate much needed additional work.